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[Background] Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46., [Methods] This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters., [Discussion] NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz’s capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression., We thank the Spanish Niemann-Pick Foundation for providing financial support. We also thank the Bellvitge University Hospital, IDIBELL and CERCA Program/Generalitat de Catalunya for institutional support.

Chronic myeloid leukemia; Imatinib; Single-nucleotide polymorphisms Leucèmia mieloide crònica; Imatinib; Polimorfismes d'un sol nucleòtid Leucemia mieloide crónica; Imatinib; Polimorfismos de un sólo nucleótido Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs. This work was supported by Novartis Oncology (NF.5.1.2-3d.018/2014) and the Fundación Española de Hematología y Hemoterapia (FEHH-SEHH).

We report the case of a 64-year-old woman with a mediastinal relapse of a uterine cervix cancer with positive human papillomavirus, an unusual site of recurrence. She consulted because of solid and liquid dysphagia of sudden appearance. Endoscopic study and non-contrast-enhanced CT showed intraluminal esophageal stenosis with a retrograde esophageal distension. 18F-FDG PET/CT demonstrated an infiltrating hypermetabolic lesion in posterior mediastinum, middle and lower esophagus, and stomach, with no signs of local or regional relapse of the uterine neoplasm.

Medullary thyroid carcinoma (MTC) is a rare malignancy. Location of residual, recurrent, or metastatic disease is crucial to treatment management and outcome. We aimed to evaluate the use of F-FDG PET/CT in localizing MTC foci in patients with biochemical relapse.This is a retrospective cohort study. Review of 51 FDG PET/CT studies of 45 patients referred to restage MTC due to increased calcitonin (Ctn) and carcinoembryonic antigen (CEA) values at follow-up. FDG PET/CT diagnostic accuracy was determined through a patient-based analysis, using histology as criterion standard when available, or other imaging studies and clinical follow-up otherwise (mean, 4 years).There were 25 positive scans. Sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and positive likelihood ratio were 66.7%, 83.3%, 88.0%, 57.7%, 72.5%, and 4.0, respectively. Using a Ctn cutoff of 1000 pg/mL, sensitivity increased to 76.9%. There were significant differences of Ctn and CEA values between positive and negative FDG PET/CT (P0.05). Regarding true-positive studies, average SUVmax comparing locoregional and metastatic disease was at the limit of significance (P = 0.046).PET/CT can be useful to restage patients with biochemical relapse of MTC, with a better performance in higher Ctn levels. Its high positive predictive value (88%) may impact in the therapeutic management, although its low negative predictive value (57.7%) makes strict follow-up mandatory in examinations without pathologic findings.

OBJECTIVE Somatic mutations in ASXL1 seem to have a negative prognostic impact in patients with several myeloid neoplasms, including myelofibrosis (MF). The aim of this work was to determine the prevalence and profile of ASXL1 mutations in MF. METHODS We analyzed mutations in ASXL1 in 70 consecutive MF patients from 8 Spanish hospitals by means of Sanger sequencing, as well as JAK2, CALR, and MPL mutations. RESULTS ASXL1 mutations were found in 16/70 (23%) of cases, most commonly p.Gly646TrpfsX12 (5/16). Most mutations (13/16) were frameshift mutations. Of 54 ASXL1- wild-type patients, 32 (59%) had at least one single nucleotide polymorphism (SNP), 27 of them had g.78128C>T, g.79017A>C, and g.79085T>C [triple SNP (TSNP) patients]. The 5-yr overall survival probability of TSNP patients was 67% (95% CI, 43-91%) vs. 90% (95% CI, 77-100%) in ASXL1-WT patients (P = 0.152). CONCLUSION ASXL1 mutations were found in 23% of cases, p.Gly646TrpfsX12 being the most frequent. About 85% of mutations were found only in individual cases and 46% had not previously been reported, a pattern also seen in other series. Fifty percent of ASXL1-WT patients had a combination of three specific SNPs that might have a prognostic correlation that needs to be determined in larger series.

Resumen Objetivo Evaluar el papel de la positron emission tomography (PET, «tomografia por emision de positrones») combinada con la tomografia computarizada (TC) en la evaluacion inicial y valoracion de la respuesta en el linfoma cerebral primario (LCP). Material y metodo Se incluyeron 14 pacientes (8 varones), con una mediana de edad de 59,5 anos, diagnosticados de un LCP de novo . A todos ellos se les realizo una resonancia magnetica (RM) y una PET-TC cerebral en la evaluacion inicial. En 7 de ellos se realizo una PET-TC en la valoracion de la respuesta. Resultados La PET-TC en el momento del diagnostico mostro 31 focos hipermetabolicos, y la RM 47 lesiones, con un grado de concordancia bueno (k = 0,61; p = 0,005). En la valoracion de la respuesta, la correlacion entre ambas pruebas fue muy buena, siendo la PET-TC de ayuda en categorizar lesiones residuales de la RM. La supervivencia global a los 2 anos de los casos con PET-TC negativa frente a positiva fue de 100 y 37,5%, respectivamente (p = 0,045). Conclusiones La PET-TC es una tecnica util en la evaluacion inicial del LCP. Detecta menor numero de lesiones infracentimetricas que la RM, con una concordancia buena entre ambas pruebas. Es eficaz en la valoracion de lesiones residuales postratamiento. Son necesarios estudios prospectivos para confirmar su posible valor pronostico.

Purpose The evaluation of bone marrow infiltration (BMI) is of crucial importance in the staging of lymphoma. Although bone marrow biopsy (BMB) is the reference standard for the evaluation of BMI, it has limitations. PET/CT has become an excellent tool in staging of lymphoma, and bone marrow uptake is correlated with the involvement of lymphoma. The aim of this study was to assess the utility of PET/CT and its concordance with BMB in the detection of BMI in patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). Patients and methods One hundred forty-seven patients with DLBCL (84) and HL (63) were referred for a PET/CT and a BMB (unilateral) at the initial staging. The reference standard was BMB. Results Bone marrow infiltration was detected by PET/CT in 39 (26%) and by BMB in 21 (14%) cases. There was concordance between PET/CT and BMB in 128 patients (87%) (74 DLBCL, 54 HL), 21 with positive PET/CT and BMB results and 107 with negative PET/CT and BMB results. Discordant results were observed in 19 patients (14%); 18 of them with positive PET/CT and negative standard BMB results (not performed in active sites). The sensitivity, specificity, accuracy, as well as positive and negative predictive values of FDG-PET/CT for the detection of BMI were 95%, 86%, 87%, 54%, and 99%, respectively. Conclusions PET/CT detects more bone marrow involvement in DLBCL and HL compared with BMB. Its good concordance with BMB makes it a complementary technique, as it helps select the biopsy site in cases with negative results.

BackgroundEltrombopag is effective and safe in chronic immune thrombocytopenia (ITP). However, clinical trials may not accurately reflect what happens in clinical practice. We evaluated the efficacy and safety of eltrombopag in primary chronic ITP in a real-world setting. MethodsA total of 164 primary patients with chronic ITP from 40 Spanish centers, who had been treated with eltrombopag, were retrospectively evaluated. ResultsThe median age of our cohort (72% women) was 63 yr (interquartile range, IQR, 45-75 yr). The median time with ITP diagnosis was 81 months (IQR, 30-192 months). The median number of therapies prior to eltrombopag was 3 (IQR, 2-4). At the time of eltrombopag start, 45 patients (30%) were receiving concomitant treatment for ITP. Forty-six patients (30%) had bleeding signs/symptoms the month before the treatment started. The median platelet count at eltrombopag initiation was 22 x 10(9)/L (IQR, 8-39 x 10(9)/L). A total of 135 patients (88.8%) achieved a platelet response. The median time to platelet response was 12 d (95% CI, 9-13 d). Maintained platelet response rate during the 15-month period under examination was 75.2%. Twenty-eight patients (18.4%) experienced adverse events, mainly grades 1-2. ConclusionEltrombopag is highly effective and well tolerated in unselected patients with primary chronic ITP.

Este articulo se ha concebido como una replica al de Llinas-Grau incluido en este numero. Para empezar, se plantea la pregunta de cual es la finalidad ultima al analizar el lenguaje infantil: ?buscar apoyo para una determinada teoria linguistica (elPrograma Minimista) o describir que conocimiento tienen los ninos del lenguaje? Desde una perspectiva teorica y filosofica, en el marco de las propuestas innatistas-racionalistas, no seria necesario dar razon de aquellas formas que se ajustan a los usos normativos, dado que formarian parte de la propia competencia. De este modo, las evidencias positivas no servirian mas que para confirmar de nuevo lo que ya conoceriamos. Aplicado a la adquisicion del lenguaje, y puesto que se atribuye al nino una Gramatica Universal (en esta ocasion en la forma de rasgos caracteristicos constitutivos de las lenguas naturales), cualquier forma linguistica que el nino utilizara constituiria una evidencia de que el nino habria adquirido dicha forma. Pero ?y la falsacion? Precisamente debido a la propia naturaleza de esta teoria, es imprescindible explicar los errores que cometen los ninos. ?Por que se alejarian de una estructura ya adquirida? En este punto, podemos dar la vuelta a la pregunta y plantearnos si hay ya una estructura. Estas consideraciones subyacen a los problemas metodologicos que se destacan en relacion al trabajo de Llinas-Grau. Se plantea que, para determinar la adquisicion de una categoria o una estructura, no basta con referir evidencias positivas unicas. Ciertamente, los errores cuentan tambien como evidencias, aunque en este caso servirian de contra-evidencias. Por ello, se propone una metodologia de analisis de las producciones infantiles radicalmente diferente y, a partir de aqui, emerge una imagen completamente distinta: los ninos basan sus emisiones en patrones posicionales productivos en torno a determinadas palabras. Asi analizadas, las producciones infantiles, mas que reflejar un uso categorial, apuntan a un trabajo a nivel de relaciones sintagmaticas entre formas linguisticas.